As a physician, I see many patients with medical conditions for which adequate therapy is not available. CB2 cannabinoid receptor-selective agonist medications may prove useful in treating some of these disease states. One is moderate-to-severe pain, where the use of opioid medications, the most effective therapy, is often limited due to concerns over addiction. In addition, opioids prescribed as analgesics are subject to diversion and abuse. We have shown that CB2 receptor-selective agonists produce strong antinociceptive effects in animal models, suggesting that they may be useful as analgesic medications for humans. Unlike cannabinoids with agonist activity at CB1 receptors, CB2 receptor-selective agonists are predicted not to produce the rewarding properties associated with drug abuse, since CB2 receptors are not found in the CNS. By reducing the need for opioids, CB2 receptor-selective medications would diminish the problem of addiction with its severe individual and social costs. CB2 receptor-selective agonists, however, are likely to have important medical applications beyond analgesia. In this proposal, we hypothesize that CB2 receptor-selective agonists will be useful in the treatment of the prevalent and challenging problems of urinary incontinence; irritable bowel syndrome, inflammatory bowel disease and visceral hypersensitivity; and opioid resistant neuropathic pain. Our goal is to combine state-of-the-art chemistry and biology to develop CB2 receptor-selective agonists as medications. Aim one will test the hypothesis that CB2 receptor-selective agonists will have therapeutically desirable properties beyond analgesic effects. We will explore the activity of CB2 receptor-selective agonists in experimental models relevant to urinary incontinence; inflammatory bowel disease and other conditions associated with sensitization or increased activity of C-fibers. We will also test the hypothesis that CB2 receptor-selective agonists will not produce a withdrawal syndrome or provide reward. Aim two will use a lead optimization strategy to improve the medicinal properties of AM1241, our structural lead compound. This will be accomplished by a structure-activity relationship study involving the systematic manipulation of each of the molecule's pharmacophoric groups using drug design principles. Novel compounds will be evaluated for their affinity at and selectivity for CB2 cannabinoid receptors in vitro and for desired properties in vivo. The successful completion of these aims will provide physicians a therapeutic option that may provide relief for patients with difficult medical conditions and decrease the use of opioids, minimizing opportunities for abuse.